Zfta–rela dictates oncogenic transcriptional programs to drive aggressive supratentorial ependymoma

Amir Arabzade, Yanhua Zhao, Srinidhi Varadharajan, Hsiao Chi Chen, Selin Jessa, Bryan Rivas, Austin J. Stuckert, Minerva Solis, Alisha Kardian, Dana Tlais, Brian J. Golbourn, Ann Catherine J. Stanton, Yuen San Chan, Calla Olson, Kristen L. Karlin, Kathleen Kong, Robert Kupp, Baoli Hu, Sarah G. Injac, Madeline NgoPeter R. Wang, Luz A. De León, Felix Sahm, Daisuke Kawauchi, Stefan M. Pfister, Charles Y. Lin, H. Courtney Hodges, Irtisha Singh, Thomas F. Westbrook, Murali M. Chintagumpala, Susan M. Blaney, Donald W. Parsons, Kristian W. Pajtler, Sameer Agnihotri, Richard J. Gilbertson, Joanna Yi, Nada Jabado, Claudia L. Kleinman, Kelsey C. Bertrand, Benjamin Deneen, Stephen C. Mack

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

More than 60% of supratentorial ependymomas harbor a ZFTA–RELA (ZRfus ) gene fusion (formerly C11orf95–RELA). To study the biology of ZRfus, we devel-oped an autochthonous mouse tumor model using in utero electroporation (IUE) of the embryonic mouse brain. Integrative epigenomic and transcriptomic mapping was performed on IUE-driven ZRfus tumors by CUT&RUN, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin sequencing, and RNA sequencing and compared with human ZRfus-driven ependymoma. In addition to direct canonical NFκB pathway activation, ZRfus dictates a neoplastic transcriptional program and binds to thousands of unique sites across the genome that are enriched with Plagl family transcription factor (TF) motifs. ZRfus activates gene expression programs through recruitment of transcriptional coactivators (Brd4, Ep300, Cbp, Pol2) that are amenable to pharmacologic inhibition. Downstream ZRfus target genes converge on developmental programs marked by Plagl TF proteins, and activate neoplastic programs enriched in Mapk, focal adhesion, and gene imprinting networks.

Original languageEnglish (US)
Pages (from-to)2200-2215
Number of pages16
JournalCancer Discovery
Volume11
Issue number9
DOIs
StatePublished - Sep 2021

ASJC Scopus subject areas

  • Oncology

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